Arylalkane-sulfonamides having endothelin-antagonist activity

ABSTRACT

The invention relates to novel aryl-alkane-sulfonamides and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as endothelin receptor antagonists.

The present invention relates to novel arylalkane-sulfonamides of thegeneral formula I and their use as active ingredients in the preparationof pharmaceutical compositions. The invention also concerns relatedaspects including processes for the preparation of the compounds,pharmaceutical compositions containing one or more compounds of thegeneral formula I and especially their use as endothelin receptorantagonists.

Endothelins (ET-1, ET-2, and ET-3) are 21-amino acid peptides producedand active in almost all tissues (Yanagisawa M et al.: Nature (1988)332:411). Endothelins are potent vasoconstrictors and importantmediators of cardiac, renal, endocrine and immune functions (McMillen MA et al.: J Am Coll Surg (1995) 180:621). They participate inbronchoconstriction and regulate neurotransmitter release, activation ofinflammatory cells, fibrosis, cell proliferation and celldifferentiation (Rubanyi G M et al.: Pharmacol Rev (1994) 46:328).

Two endothelin receptors have been cloned and characterized in mammals(ET_(A), ET₈) (Arai H et al.: Nature (1990) 348:730; Sakurai T et al.:Nature (1990) 348:732). The ET_(A) receptor is characterized by higheraffinity for ET-1 and ET-2 than for ET-3. It is predominant in vascularsmooth muscle cells and mediates vasoconstricting and proliferativeresponses (Ohlstein E H et al.: Drug Dev Res (1993) 29:108). Incontrast, the ET_(B) receptor has equivalent affinity for the 3endothelin isopeptides and binds the linear form of endothelin,tetra-ala-endothelin, and sarafotoxin S6C (Ogawa Y et al.: BBRC (1991)178:248). This receptor is located in the vascular endothelium andsmooth muscles, and is also particularly abundant in lung and brain. TheET_(B) receptor from endothelial cells mediates transient vasodilatorresponses to ET-1 and ET-3 through the release of nitric oxide and/orprostacyclin whereas the ET_(B) receptor from smooth muscle cells exertsvasoconstricting actions (Sumner M J et al.: Brit J Pharmacol (1992)107:858). ET_(A) and ET_(B) receptors are highly similar in structureand belong to the superfamily of G-protein coupled receptors.

A pathophysiological role has been suggested for ET-1 in view of itsincreased plasma and tissue levels in several disease states such ashypertension, sepsis, atherosclerosis, acute myocardial infarction,congestive heart failure, renal failure, migraine and asthma. As aconsequence, endothelin receptor antagonists have been studiedextensively as potential therapeutic agents. Endothelin receptorantagonists have demonstrated preclinical and/or clinical efficacy invarious diseases such as cerebral vasospasm following subarachnoidhemorrhage, heart failure, pulmonary and systemic hypertension,neurogenic inflammation, renal failure and myocardial infarction.

Today, no endothelin receptor antagonist is marketed yet, several are inclinical trials. However, these molecules possess a number of weaknessessuch as complex synthesis, low solubility, high molecular weight, poorpharmacokinetics, or safety problems (e.g. liver enzyme increases).

The inhibitory activity of the compounds of general formula I onendothelin receptors can be demonstrated using the test proceduresdescribed hereinafter:

For the evaluation of the potency and efficacy of the compounds of thegeneral formula I the following tests were used:

1) Inhibition of Endothelin Binding to Membranes from CHO Cells CarryingHuman ET Receptors:

For competition binding studies, membranes of CHO cells expressing humanrecombinant ET_(A) or ET_(B) receptors were used. Microsomal membranesfrom recombinant CHO cells were prepared and the binding assay made aspreviously described (Breu V., et al, FEBS Lett 1993; 334:210).

The assay was performed in 200 uL 50 mM Tris/HCl buffer, pH 7.4,including 25 mM MnCl₂, 1 mM EDTA and 0.5% (w/v) BSA in polypropylenemicrotiter plates. Membranes containing 0.5 ug protein were incubatedfor 2 h at 20° C. with 8 pM [¹²⁵I]ET-1 (4000 cpm) and increasingconcentrations of unlabelled antagonists. Maximum and minimum bindingwere estimated in samples without and with 100 nM ET-1, respectively.After 2 h, the membranes were filtered on filterplates containing GF/Cfilters (Unifilterplates from Can berra Packard S. A. Zürich,Switzerland). To each well, 50 uL of scintillation cocktail was added(MicroScint 20, Can berra Packard S. A. Zürich, Switzerland) and thefilter plates counted in a microplate counter (TopCount, Can berraPackard S. A. Zürich, Switzerland).

All the test compounds were dissolved, diluted and added in DMSO. Theassay was run in the presence of 2.5% DMSO which was found not tointerfere significantly with the binding. IC₅₀ was calculated as theconcentration of antagonist inhibiting 50% of the specific binding ofET-1. For reference compounds, the following IC₅₀ values were found:ET_(A) cells: 0.075 nM (n=8) for ET-1 and 118 nM (n=8) for ET-3; ET_(B)cells: 0.067 nM (n=8) for ET-1 and 0.092 nM (n=3) for ET-3.

The IC₅₀ values obtained with compounds of general formula I are givenin Table 1.

TABLE 1 Compound of Example IC₅₀ ET_(A) [nM] IC₅₀ ET_(B) [nM] Example 1 27 6650 Example 2  20 899 Example 5  3 323 Example 7  4 3310 Example 109 2410 Example 13 4 3680 Example 14 6 2230 Example 19 3 1930 Example 2910 406 Example 39 3 261 Example 46 7 2360 Example 47 24 2720 Example 494 2490 Example 52 5 1770 Example 61 10 1140 Example 71 115 >10000Example 81 24 8242) Inhibition of Endothelin-Induced Contractions on Isolated Rat AorticRings (ET_(A) Receptors) and Rat Tracheal Rings (ET_(B) Receptors):

The functional inhibitory potency of the endothelin antagonists wasassessed by their inhibition of the contraction induced by endothelin-1on rat aortic rings (ET_(A) receptors) and of the contraction induced bysarafotoxin S6c on rat tracheal rings (ET_(B) receptors). Adult Wistarrats were anesthetized and exsanguinated. The thoracic aorta or tracheawere excised, dissected and cut in 3–5 mm rings. Theendothelium/epithelium was removed by gentle rubbing of the intimalsurface. Each ring was suspended in a 10 ml isolated organ bath filledwith Krebs-Henseleit solution (in mM; NaCl 115, KCl 4.7, MgSO₄ 1.2,KH₂PO₄ 1.5, NaHCO₃ 25, CaCl₂ 2.5, glucose 10) kept at 37° C. and gassedwith 95% O₂ and 5% CO. The rings were connected to force transducers andisometric tension was recorded (EMKA Technologies SA, Paris, France).The rings were stretched to a resting tension of 3 g (aorta) or 2 g(trachea). Cumulative doses of ET-1 (aorta) or sarafotoxin S6c (trachea)were added after a 10 min incubation with the test compound or itsvehicle. The functional inhibitory potency of the test compound wasassessed by calculating the concentration ratio, i.e. the shift to theright of the EC₅₀ induced by different concentrations of test compound.EC₅₀ is the concentration of endothelin needed to get a half-maximalcontraction, pA₂ is the negative logarithm of the antagonistconcentration which induces a two-fold shift in the EC₅₀ value.

The pA₂ values obtained with compounds of formula I are given in Table2.

TABLE 2 Compound of Example pA₂ (aortic rings) pA₂ (trachea) Example 58.38 7.02 Example 7 8.83 7.07 Example 8 7.43 — Example 34 7.67 — Exampl61 7.83 7.07 Example 75 7.76 —

Because of their ability to inhibit the endothelin binding, thedescribed compounds can be used for treatment of diseases which areassociated with an increase in vasoconstriction, proliferation orinflammation due to endothelin. Examples of such diseases arehypertension, coronary diseases, cardiac insufficiency, renal andmyocardial ischemia, renal failure, cerebral ischemia, dementia,migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portalhypertension and pulmonary hypertension. They can also be used foratherosclerosis, prevention of restenosis after balloon or stentangioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatichypertrophy, erectile dysfunction, hearing loss, amaurosis, chronicbronchitis, asthma, gram negative septicemia, shock, sickle cell anemia,glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis ofdiabetic complications, complications of vascular or cardiac surgery orafter organ transplantation, complications of cyclosporin treatment,pain as well as other diseases presently known to be related toendothelin.

The compounds can be administered orally, rectally, parenterally, e.g.by intravenous, intramuscular, subcutaneous, intrathecal or transdermaladministration or sublingually or as ophthalmic preparation oradministered as aerosol. Examples of applications are capsules, tablets,orally administered suspensions or solutions, suppositories, injections,eye-drops, ointments or aerosols/nebulizers.

Preferred applications are intravenous, intramuscular, or oraladministrations as well as eye drops. The dosage used depends upon thetype of the specific active ingredient, the age and the requirements ofthe patient and the kind of application. Generally, dosages of 0.1–50mg/kg body weight per day are considered. The preparations withcompounds can contain inert or as well pharmacodynamically activeexcipients. Tablets or granules, for example, could contain a number ofbinding agents, filling excipients, carrier substances or diluents.

The present invention relates to arylethene-sulfonamides of the generalformula I,

wherein

-   R¹ and R² represent aryl; heteroaryl;-   R³ represents phenyl; mono-, di- or tri-substituted phenyl    substituted with lower alkyl, lower alkenyl, lower alkynyl, phenyl,    lower alkoxy, amino, lower alkylamino, amino-lower alkyl,    trifluoromethyl, trifluoromethoxy, halogen, lower alkylthio,    hydroxy, hydroxy-lower alkyl, cyano, carboxyl, lower alkanoyl,    formyl; benzofuranyl; aryl; heteroaryl;-   R⁴ represents hydrogen; halogen; trifluoromethyl; lower alkyl; lower    alkyl-amino; lower alkoxy; lower alkyl-sulfono; lower    alkyl-sulfinyl; lower alkylthio; lower alkylthio-lower alkyl;    hydroxy-lower alkyl; lower alkyl-oxy-lower alkyl; hydroxy-lower    alkyl-oxy-lower alkyl; hydroxy-lower alkyl-amino; lower    alkyl-amino-lower alkyl; amino; di-lower alkyl-amino;    [N-(hydroxy-lower alkyl)-N-(lower alkyl)]-amino; aryl; aryl-amino;    aryl-lower alkyl-amino; aryl-thio; aryl-lower alkyl-thio; aryloxy;    aryl-lower alkyl-oxy; aryl-lower alkyl; aryl-sulfinyl; heteroaryl;    heteroaryl-oxy; heteroaryl-lower alkyl-oxy; heteroaryl-amino;    heteroaryl-lower alkyl-amino; heteroaryl-thio; heteroaryl-lower    alkyl-thio; heteroaryl-lower alkyl; heteroaryl-sulfinyl;    heterocyclyl; heterocyclyl-lower alkyl-oxy; heterocyclyl-oxy;    heterocyclyl-amino; heterocyclyl-lower alkyl-amino;    heterocyclyl-thio; heterocyclyl-lower alkylthio; heterocyclyl-lower    alkyl; heterocyclyl-sulfinyl; cycloalkyl; cycloalkyl-oxy;    cycloalkyl-lower alkyl-oxy; cycloalkyl-amino; cycloalkyl-lower    alkyl-amino; cycloalkyl-thio; cycloalkyl-lower alkyl-thio;    cycloalkyl-lower alkyl; cycloalkyl-sulfinyl;-   X represents oxygen; sulfur; NH; CH₂ or a bond;-   Y represents oxygen; sulfur or —NH—;-   Z represents oxygen; sulfur, —NH— or a bond;-   Q represents —(CH₂)_(k)—; —(CH₂)_(m)—C≡C—(CH₂)_(p)—, in case p    represents 0(zero), Z represents a bond; —CH₂-cyclopropylen-CH₂—;-   k represents the numbers 2, 3; 4, 5, or 6;-   m represents the numbers 1, 2, or 3;-   p represents the numbers 0, 1, 2 or 3;-   n represents the numbers 1, 2, or 3;-   and pure diastereomers, mixtures of diastereomers, diastereomeric    racemates, mixtures of diastereomeric racemates and the meso-forms    and pharmaceutically acceptable salts thereof.

In the definitions of the general formula I—if not otherwise stated—theexpression lower alkyl or lower alkoxy means straight and branched chaingroups with one to seven carbon atoms, preferably 1 to 4 carbon atoms.Examples of lower alkyl and lower alkoxy groups are methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl,hexyl, heptyl, methoxy, ethoxy, propoxy, n-butoxy, iso-butoxy,sec.-butoxy and tert.-butoxy. Lower alkylendioxy-groups are preferablymethylene-dioxy, ethylene-dioxy, propylene-dioxy and butylen-dioxygroups. Examples of lower alkanoyl-groups are acetyl, propanoyl andbutanoyl. Lower alkenylen means e.g.vinylen, propenylen and butenylen.Lower alkenyl and lower alkynyl means groups like ethylene, propylen,butylen, 2-methyl-propenyl, and ethinylen, propinylen, butinylen,pentinylen, 2-methyl-pentinylen etc. Lower alkenyloxy means allyloxy,vinyloxy, propenyloxy and the like. The expression cycloalkyl means asaturated cyclic hydrocarbon ring with 3 to 7 carbon atoms, e.g.cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, whichmay be substituted with lower alkyl, hydroxy-lower alkyl, amino-loweralkyl, lower alkoxy-lower alkyl and lower alkenylen groups. Theexpression heterocyclyl means saturated or partially unsaturated four,five-, six- or seven-membered rings containing one or two nitrogen,oxygen or sulfur atoms which may be the same or different and whichrings may be adequatly substituted with lower alkyl, amino, nitro,hydroxy, lower alkoxy, e.g. piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl,pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, dihydroimidazolyl,dihydropyrazolyl, pyrazolidinyl, 5-oxo-1,2,4-oxadiazolyl,5-oxo-1,2,4-thiadiazolyl, 5-thioxo-1,2,4-oxadiazolyl,2-oxo-1,2,3,5-oxathiadiazolyl etc. (e.g.[7]) and substituted derivativesof such rings with substituents as outlined above. The expressionheteroaryl means six-membered aromatic rings containing one to fournitrogen atoms, benzofused six-membered aromatic rings containing one tothree nitrogen atoms, five-membered aromatic rings containing one oxygenor one nitrogen or one sulfur atom, benzo-fused five-membered aromaticrings containing one oxygen or one nitrogen or one sulfur atom, fivemembered aromatic rings containing an oxygen and nitrogen atom and benzofused derivatives thereof, five membered aromatic rings containing asulfur and a nitrogen atom and benzo fused derivatives thereof,five-membered aromatic rings containing two nitrogen atoms and benzofused derivatives thereof, five membered aromatic rings containing threenitrogen atoms and benzo fused derivatives thereof or the tetrazolylring; e.g. furanyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, indolyl,quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, thiazolyl,isothiazolyl, pyridazinyl, oxazolyl, isoxazolyl, etc. whereby such ringsmay be substituted with lower alkyl, lower alkenyl, amino, amino-loweralkyl, halogen, hydroxy, lower alkoxy, trifluoromethoxy,trifluoromethyl, carboxyl, carboxamidyl, thioamidyl, amidinyl, loweralkoxy, cyano, hydroxy-lower alkyl, lower alkoxy-lower alkyl or anotherheteroaryl- (preferrably tetrazolyl) or heterocyclyl-ring (preferrably5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-triazolyl,5-oxo-1,2,4-thiadiazolyl, 5-thioxo-1,2,4-oxadiazolyl or2-oxo-1,2,3,5-oxathiadiazolyl (e.g. [7])). The expression arylrepresents unsubstituted as well as mono-, di- or tri-substitutedaromatic rings with 6 to 10 carbon atoms like phenyl or naphthyl ringswhich may be substituted with aryl, halogen, hydroxy, lower alkyl, loweralkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, loweralkynyl-lower alkyl-oxy, lower alkenylen, lower alkylenoxy, loweralkylenoxy or lower alkylendioxy forming with the phenyl ring a five- orsix-membered ring, hydroxy-lower alkyl, hydroxy-lower alkenyl,hydroxy-lower alkyl-lower alkynyl, lower alkoxy-lower alkyl, loweralkoxy-lower alkoxy, trifluoromethyl, trifluoromethoxy, cycloalkyl,hydroxy-cycloalkyl, heterocyclyl, heteroaryl.

It is understood that the substituents outlined relative to theexpressions cycloalkyl, heterocyclyl, heteroraryl and aryl have beenomitted in the definitions of the general formulae I to V in claims 1 to11 for clarity reasons but the definitions in formulae I to V and inclaims 1 to 11 should be read as if they are included therein.

Especially preferred compounds are compounds of general formula Iwherein R³ represents phenyl or mono-substituted phenyl substituted withlower alkoxy, especially methoxy and X represents oxygen.

A second group of especially preferred compounds of general formula Iare the compounds wherein R³ represents phenyl or mono-substitutedphenyl substituted with lower alkoxy, especially methoxy, and wherein X,Y and Z represent oxygen.

A third group of especially preferred compounds of general formula I arethe compounds wherein R³ represents phenyl or mono-substituted phenylsubstituted with lower alkoxy, especially methoxy, and wherein X, Y andZ represent oxygen and Q represents —(CH₂)_(k)— with k=2 or 3.

A fourth group of especially preferred compounds of general formula Iare the compounds wherein R² represents heteroaryl, R³ represents phenylor mono-substituted phenyl substituted with lower alkoxy, especiallymethoxy, X, Y and Z represent oxygen and Q represents —(CH₂)_(k)— withk=2 or 3.

A fifth group of especially preferred compounds of general formula I arethe compounds wherein R² represents heteroaryl, R³ represents phenyl ormono-substituted phenyl substituted with halogen, lower alkyl, loweralkenyl, methoxy, amino, lower alkyl-amino, lower alkyl-thio, hydroxy,hydroxymethyl and lower alkanoyl; X, Y and Z represent oxygen, Qrepresents —(CH₂)₂—.

Another group of preferred compounds are compounds of formula II

wherein R¹, R², R³, R⁴, Y, Q, Z, and n are as defined in general formulaI above, and pharmaceutically acceptable salts of compounds of formulaII.

Also preferred are compounds of formula III

wherein R¹, R², R⁴, Y, Q and Z and n are as defined in general formula Iabove, and pharmaceutically acceptable salts of compounds of formulaIII.

Also preferred are compounds of formula IV

wherein R¹, R², R⁴, Q, and n are as defined in general formula I above,and pharmaceutically acceptable salts of compounds of formula IV.

Another especially preferred group of compounds are compounds of formulaV

wherein R¹ and R² are as defined in general formula I above, andpharmaceutically acceptable salts thereof.

Especially preferred compounds among the group of compounds of formula Vare those wherein R² represents heteroaryl.

The expression pharmaceutically acceptable salts encompasses eithersalts with inorganic acids or organic acids like hydrohalogenic acids,e.g. hydrochloric or hydrobromic acid; sulfuric acid, phosphoric acid,nitric acid, citric acid, formic acid, acetic acid, maleic acid,tartaric acid, methylsulfonic acid, p-toluolsulfonic acid and the likeor in case the compound of formula I is acidic in nature with aninorganic base like an alkali or earth alkali base, e.g. sodiumhydroxide, potassium hydroxide, calcium hydroxide etc.

The compounds of the general formula I might have one or more asymmetriccarbon atoms and may be prepared in form of optically pure enantiomersor diastereomers, mixtures of enantiomers or diastereomers,diastereomeric racemates, mixtures of diastereomeric racemates and alsoin the meso-form. The present invention encompasses all these forms.Mixtures may be separated in a manner known per se, i.e. by columnchromatography, thin layer chromatography, HPLC, crystallization etc.

Because of their ability to inhibit the endothelin binding, thedescribed compounds of the general formula I and their pharmaceuticallyacceptable salts may be used for treatment of diseases which areassociated with an increase in vasoconstriction, proliferation orinflammation due to endothelin. Examples of such diseases arehypertension, coronary diseases, cardiac insufficiency, renal andmyocardial ischemia, renal failure, cerebral ischemia, dementia,migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portalhypertension and pulmonary hypertension. They can also be used foratherosclerosis, prevention of restenosis after balloon or stentangioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatichypertrophy, erectile dysfunction, hearing loss, amaurosis, chronicbronchitis, asthma, gram negative septicemia, shock, sickle cell anemia,glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis ofdiabetic complications, complications of vascular or cardiac surgery orafter organ transplantation, complications of cyclosporin treatment,pain, as well as other diseases presently known to be related toendothelin.

These compositions may be administered in enteral or oral form e.g. astablets, dragees, gelatine capsules, emulsions, solutions orsuspensions, in nasal form like sprays or rectically in form ofsuppositories. These compounds may also be administered inintramuscular, parenteral or intravenous form, e.g. in form ofinjectable solutions.

These pharmaceutical compositions may contain the compounds of formula Ias well as their pharmaceutically acceptable salts in combination withinorganic and/or organic excipients which are usual in thepharmaceutical industry like lactose, maize or derivatives thereof,talcum, stearinic acid or salts of these materials.

For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquidpolyols etc. may be used. For the preparation of solutions and sirupse.g. water, polyols, saccharose, glucose etc. are used. Injectables areprepared by using e.g. water, polyols, alcohols, glycerin, vegetableoils, lecithin, liposomes etc. Suppositories are prepared by usingnatural or hydrogenated oils, waxes, fatty acids (fats), liquid orhalf-liquid polyols etc.

The compositions may contain in addition preservatives, stabilisationimproving substances, viscosity improving or regulating substances,solubility improving substances, sweeteners, dyes, taste improvingcompounds, salts to change the osmotic pressure, buffer, anti-oxidantsetc.

The compounds of formula I may also be used in combination with one ormore other therapeutically useful substances e.g. α- and β-blockers likephentolamine, phenoxybenzamine, atenolol, propranolol, timolol,metoprolol, carteolol etc.; Vasodilators like hydralazine, minoxidil,diazoxide, flosequinan etc.; Calcium-antagonists like diltiazem,nicardipine, nimodipine, verapamil, nifedipine etc.; ACE-inhibitors likecilazapril, captopril, enalapril, lisinopril etc.; Potassium activatorslike pinacidil etc.; Angiotensin II antagonists; Diuretics likehydrochlorothiazide, chlorothiazide, acetolamide, bumetanide,furosemide, metolazone, chlortalidone etc.; Sympatholitics likemethyldopa, clonidine, guanabenz, reserpine etc.; and other therapeuticswhich serve to treat high blood pressure or any cardiac disorders.

The dosage may vary within wide limits but should be adapted to thespecific situation. In general the dosage given daily in oral formshould be between about 3 mg and about 3 g, preferably between about 10mg and about 1 g, especially preferred between 5 mg and 300 mg, peradult with a body weight of about 70 kg. The dosage should beadministered preferably in 1 to 3 doses per day which are of equalweight. As usual children should receive lower doses which are adaptedto body weight and age.

Compounds of the general formula I of the present invention can beprepared according to the general sequence of reactions outlined below.For simplicity and clarity reasons sometimes only parts of the syntheticpossibilities which lead to compounds of general formula I aredescribed. The literature references given in brackets [ ] are set forthat the end of this paragraph.

Possibility A:

The desired compounds of general formula I can be prepared by reacting acompound of the formula 1:

wherein G¹ is a reactive residue, preferentially a chlorine atom, andthe other symbols are as defined in general formula I above, with acompound of the formula 2:

wherein the symbols are the same as defined in general formula I above,or a salt thereof.Possibility B:

The compounds of general formula I may also be prepared by reacting acompound of formula 3:

wherein the symbols are the same as defined in general formula I above,or a salt thereof, with a compound of the formula 4G²—R²  Formula 4wherein G² is a reactive residue, such as a halogen atom, and R² is asdefined in general formula I above.Possibility C:

The compounds of general formula I may also be prepared by reacting acompound of the formula 5:

Wherein G³ is a lower alkylsulfonyl group or a phenylsulfonyl group or ahalogen atom, and the other symbols are the same as described in generalformula I above, or a salt thereof, with a compound of the formula 6:H—R⁴  Formula 6wherein R⁴ is as defined in general formula I above, or a salt thereof.

For possibilities A to C see also [5].

The amidines 8 were synthesized applying standard methodology [1] byreaction of the appropriate nitrile 7 either with sodium methylate inmethanol followed by addition of ammonium chloride or by reaction withlithium hexamethyldisilazane followed by addition of hydrochloric acidin i-propanol. The 2-substituted malonic esters 10 were preparedaccording to published procedures [2] by reacting dimethylchloromalonate(9) with the appropriate alcohol 11 in acetone and potassium carbonateas base. The compounds 10 were dissolved in methanol and sodiummethylate was added and stirring was continued for about 30 min followedby the addition of an amidine derivative 8. Stirring at ambienttemperature was continued for another 8 h. After acidic work up the4,6-dihydroxypyrimidines 12 could be isolated in yields of 70 to 90%[2]. Compounds 12 or the tautomeric form thereof were transformed intothe dichloro derivatives 13 with phosphorus oxychloride in the presenceof N,N-dimethylaniline at elevated temperatures (60–120° C.) in yieldsof 40 to 75% [3]. In some cases better yields were obtained by additionof PCI₅ or benzyl-triethylammoniumchloride. The dichlorides 13 werereacted with an excess of the appropriate sulfonamide potassium salt 15(prepared according to standard methodology from the sulfochlorides 14(for the preparation of 14 see e.g. [9], [10]) in DMSO at rt to give thepyrimidines 16 in yields of 70 to 90% either after recrystallizationfrom EA/diethylether or chromatography through silica gel withEA/heptane. The pyrimidine derivatives 16 are the key intermediateswhich can be transformed to the desired final products of generalformula I either by applying procedures outlined under Possibility A orthey can be transformed to the derivatives 18 by reaction with adi-hydroxy-compound represented by formula 17 in the presence of a basesuch as sodium hydride in a solvent like THF at rt to 90° C. and canthen be transformed to final compounds according to the general formulaI by applying procedures outlined under Possibility B above.

For further experimental descriptions see [1], [2], [3], [6].

The synthesis of compounds with X, Y or Z being other groups thanoxygen, can be carried out in analogous manners.

For further experimental descriptions see [1], [2], [3], [5] [6]. Forthe substitution of the sulfono-group, see especially [5].

The synthesis of compounds with X, Y or Z being another group thanoxygen, can be carried out in analogous procedures.

In the schemes 1 to 3 the symbols represent the same as defined ingeneral formula I above.

-   [1] W. Göhring, J. Schildknecht, M. Federspiel; Chimia, 50 (1996),    538–543.-   [2] W. Neidhart, V. Breu, D. Bur, K. Burri, M. Clozel, G. Hirth, M.    Müller, H. P. Wessel, H. Ramuz; Chimia, 50 (1996), 519–524 and    references cited there.-   [3] W. Neidhart, V. Breu, K. Burri, M. Clozel, G. Hirth, U.    Klinkhammer, T. Giller, H. Ramuz; Bioorg. Med. Chem. Lett., 7    (1997), 2223–2228. R. A. Nugent, S. T. Schlachter, M. J.    Murphy, G. J. Cleek, T. J. Poel, D. G. Whishka, D. R. Graber, Y.    Yagi, B. J. Keiser, R. A. Olmsted, L. A. Kopta, S. M. Swaney, S. M.    Poppe, J. Morris, W. G. Tarpley, R. C. Thomas; J. Med. Chem., 41    (1998), 3793–3803.-   [4] J. March; Advanced Organic Chemistry, 4th Ed., 1994, p. 499 and    references cited there.-   [5] EP 0 743 307 A1; EP 0 658 548 B1; EP 0 959 072 A1 (Tanabe    Seiyaku)-   [6] EP 0 633 259 B1; EP 0 526 708 A1; WO 96/19459 (F.    Hoffmann-LaRoche)-   [7] for the Synthesis of 5-membered heterocycles see: Y. Kohara et    al; J. Med. Chem., 39 (1996), 5228–5235 and references cited there.-   [8] EP 0 882 719 A1 (Yamanouchi Pharmaceutical Co., Ltd)-   [9] Z. Zhong,J. A. Bibbs, W. Yuan, C.-H. Wong, J. Am. Chem. Soc.    113, (1991), 2259–2263-   [10] D. J. Kempf, L. Codavoci, X. C. Wang, W. E. Kohlbrenner, N. E.    Wideburg, A. Saldivar, S. Vasavanonda, K. C. Marsh, P. Bryant, H. L.    Sham, B. E. Green, D. A. Betebenner, J. Erikson, D. W. Norbeck, J.    Med. Chem. 36 (1993), 320–330

REFERENTIAL EXAMPLES (SYNTHESIS OF PRECURSORS)

List of abbreviations: CyHex cyclohexane DCM dichloromethane DME1,2-dimethoxyethane DMF dimethylformamide DMSO dimethylsulfoxide EAethyl acetate Hex hexane HV high vacuum conditions MCPBAm-chloroperbenzoic acid min minutes rt room temperature THFtetrahydrofurane sat. saturated t_(R) retention time

The following referential examples illustrate the invention but do notat all limit the scope thereof.

The following compounds were prepared according to the proceduredescribed above and shown in Schemes 1 to 3. All compounds werecharacterized by ¹H-NMR (300 MHz) and occasionally by ¹³C-NMR (75 MHz)(Varian Oxford, 300 MHz; chemical shifts are given in ppm relative tothe solvent used; multiplicities: s=singlet, d=doublet, t=triplet;m=multiplett, coupling constants J in Hz), by LC-MS (Waters Micromass;ZMD-plafform with ESI-probe with Alliance 2790 HT; Colum: 2×30 mm,Gromsil ODS4, 3μm, 120A; Gradient: 0–100% acetonitril in water, 6 min,with 0.05% formic acid, flow: 0.45 ml/min; t_(R) is given in min.), byTLC (TLC-plates from Merck, Silica gel 60 F₂₅₄) and occasionally bymelting point. All temperatures are stated in ° C.

Referential Example 1

a) Sodium methylate (17 g) was dissolved in methanol (600 ml) at 0° C.2-p-tolyl-malonic acid diethyl ester (24.5 ml, commercially availablefrom Aldrich), dissolved in 150 ml methanol, was added within 30 min.Stirring was continued for 1 h while slowly warming the mixture to rt.Formamidine hydrochloride (9.9 g, commercially available from Fluka) wasadded and stirring was continued for 16 h. The solvent was evaporatedand 2 M hydrochloric acid (200 ml) was added to the residue followed byslow addition of 10 M sodium hydroxide to adjust the pH to 5. Theprecipitated product was filtered off and washed subsequently with waterand diethylether and dried to give 5-p-tolyl-pyrimidine-4,6-diol (17.7g). ¹H-NMR (300 MHz, d6-DMSO): 8.0(s, 1H); 7.4(d, 2H); 7.1(d, 2H);2.25(s, 3H).

b) 5-p-tolyl-pyrimidine-4,6-diol (17.2 g) was dissolved in phosphorusoxychloride (250 ml) and N,N-dimethylaniline (25 ml) was added. Themixture was stirred at 70° C. for 16 h, then concentrated in vacuo. Theresidue was poured onto ice-water and extracted with diethylether (3×).The combined organic extracts were washed with 1N hydrochloric acid andwith saturated sodium chloride solution, dried over magnesium sulfate,filtered and the filtrate was evaporated. The crude brown material wasrecrystallized from i-propanol to give 4,6-dichloro-5-p-tolyl-pyrimidine(13.5 g). ¹H-NMR (CDCl₃): 8.78(s, 1H); 7.35(d, 2H); 7.20(d, 2H); 2.41(s,3H).

c) 2-Phenylethanesulfonyl chloride was prepared by oxidisingphenylethylmercaptan with N-chlorosuccinimide following the proceduregiven in [9].

d) A solution of 2-phenylethanesulfonyl chloride (40.94 g) in THF (250ml) was cooled to −20° C. before it was treated with sat. aq. ammonia(50 ml). The brown suspension was stirred at rt for 16 h. The mixturewas neutralised with aq. HCl and the organic solvent was evaporated. Theremaining suspension was diluted with water and extracted four timeswith EA. The organic layers were combined and evaporated to give2-phenyl-ethanesulfonic acid amide (33.06 g) as orange solid. ¹H-NMR(300MHz, CDCl₃): 3.15–3.21(m, 2H), 3.38–3.45(m, 2H), 4.59(s br, 2H),7.21–7.37(m, 5H).

e) To a solution of 2-phenyl-ethanesulfonic acid amide (33.06 g) inmethanol (300 ml) was added K.-tert.butylate (20.03 9). The resultingsolution was stirred for 15 min before it was evaporated. The residuewas washed with diethyl ether (400 ml) and dried under high vacuum togive 2-phenyl-ethanesulfonic acid amide potassium salt (37.93 g) as anorange powder.

f) A solution of 2-phenyl-ethanesulfonic acid amide potassium salt (3.0g), 4,6-dichloro-5-p-tolyl-pyrimidine (2.15 g) and Hunig's base (1.57ml) in DMSO (50 ml) was stirred at rt for 20 h before it was dilutedwith water (500 ml) and extracted twice with diethyl ether (250 ml). Theaqueous phase was acidified with acetic acid. The resulting suspensionwas cooled to 5° C. and filtered. The solid material was washed withwater and diethyl ether, and dried at 40° C. under high vacuum to give2-phenyl-ethanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide(2.08 g) as a grey powder. LC-MS: t_(R)=5.23 min, [M+1]⁺=388.18,[M−1]⁻=386.14.

g) 2-Phenyl-ethanesulfonic acid(6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (850 mg) was added to asolution of K-tert. butylate (1.1 g) in ethylene glycol (15 ml). Themixture was stirred at 120° C. for 27 h before it was diluted with water(100 ml), acidified with 10% aq. citric acid (13 ml). The resultingprecipitate was collected, washed with water and diethyl ether and driedto give 2-phenyl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (716 mg) as abeige powder. LC-MS: t_(R)=4.44 min, [M+1]⁺=414.18, [M−1]⁻=412.13.

Referential Example 2

a) To a solution of sodium (0.23 g) in methanol (40 ml) was added4-cyanopyridine (10.62 g) at room temperature. Stirring was continuedfor 6 h followed by the addition of ammoniumchloride (5.9 g) andstirring was continued for another 10 h. Then diethylether (120 ml) wasadded and the precipitate was filtered off after 30 min and washed oncewith diethylether (20 ml). The product was dried under high vacuum.4-Amidino-pyridine hydrochloride (14.95 g) was obtained as a whitepowder.

b) A solution of sodium methylate (6.8 g) in methanol (200 ml) wascooled to 0° C. A solution of diethyl 2-(p-tolyl)-malonate (10.3 g) inmethanol (50 ml) was slowly added. Upon completion of the addition thesolution was allowed to come to room temperature and 4-amidino-pyridinehydrochloride (7.57 g) was added. The mixture was stirred at roomtemperature for 16 h. Eventually, the solvent was removed under reducedpressure and the remaining residue was dissolved in 2 M hydrochloricacid. The solution was extracted with diethyl ether, then adjusted to pH5 with 10 M sodium hydroxide solution. A precipitate formed. Theprecipitate was collected, washed with cold water and dried at 60° C.under high vacuum. This gave4,6-dihydroxy-2-(4-pyridyl)-5-(p-tolyl)-pyrimidine (8.77 g) (or atautomer) as orange crystals.

c) To a mixture of 5-(p-tolyl)-4,6-dihydroxy-pyrimidine (8.0 g) andPOCl₃ (100 ml), diethylamine (25 ml) was added at room temperature. Themixture was stirred for 16 h at 60° C. The excess of POCl₃ was distilledoff under reduced pressure. The remaining oil was dissolved in DCM (300ml) and treated with water (300 ml). The aqueous layer was separated andextracted three times with DCM. The combined organic layers were washedwith water and brine, dried over MgSO₄ and evaporated. The resultingresidue was suspended in isopropanol. The solid material was collected,washed with isopropanol, and diethyl ether and dried to give4,6-dichloro-2-(4-pyridyl)-5-(p-tolyl)-pyrimidine (7.2 g) as a whitecrystalline powder. LC-MS: t_(R)=5.49 min, [M+1]⁺=315.89.

d) A solution of 4,6-dichloro-2-(4-pyridyl)-5-(p-tolyl)-pyrimidine (1.5g), 2-phenyl-ethanesulfonic acid amide potassium salt (1.44 g,Referential Example 1e) and Hunig's base (1 ml) in DMSO (20 ml) wasstirred at rt for 24 h before it was diluted with water (150 ml) andextracted twice with diethyl ether. The aqueous layer was acidified withacetic acid. The precipitate was collected, and further purified bycolumn chromatography on silica gel eluting with hexane:EA 1:1 to give2-phenyl-ethanesulfonic acid(6-chloro-2-pyridin-4-yl-5-p-tolyl-pyrimidin-4-yl)-amide (480 mg) as afoam. LC-MS: t_(R)=5.08 min, [M+1]⁺=465.13, [M−1]⁻=462.96.

e) 2-Phenyl-ethanesulfonic acid(6-chloro-2-pyridin-4-yl-5-p-tolyl-pyrimidin-4-yl)-amide (480 mg) wasadded to a solution of K-tert. butylate (580 mg) in ethylene glycol (5ml). The mixture was stirred at 11° C. for 72 h before it was dilutedwith water (100 ml), acidified with 10% aq. citric acid (13 ml). Theresulting precipitate was collected, washed with water and diethyl etherand dried to give 2-phenyl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-2-pyridin-4-yl-5-p-tolyl-pyrimidin-4-yl]-amide asa beige powder. LC-MS: t_(R)=4.17 min, [M+1]⁺=491.24, [M−1]⁻=489.08.

Referential Example 3

2-Phenyl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-[2,2]bipyrimidinyl-4-yl]-amide wasprepared following the procedures given in Referential Example 2starting from 2-amidino-pyrimidine hydrochloride (e.g. EP 0 526 708A1)-. LC-MS: t_(R)=4.42 min, [M+1]⁺=492.30, [M−1]⁻=490.27.

Referential Example 4

2-Phenyl-ethanesulfonic acid[5-(4-bromo-phenyl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide wasprepared in analogy to Referential Example 15 using 4-bromophenylaceticacid methyl ester instead of 4-chlorophenylacetic acid methyl ester instep a) and 2-phenyl-ethanesulfonic acid amide potassium salt instead of2-thiophen-2-yl-ethanesulfonic acid amide potassium salt in step d).LC-MS: t_(R)=4.60 min, [M+1]⁺=480.07, [M−1]⁻=475.76.

Referential Example 5

a) (In analogy to a procedure given in J. Am. Chem. Soc. 122 (2000),1360-1370.) To a suspension of Pd(OAc)₂ (455 mg),2-(di-tert.-butylphosphino)-biphenyl (1.21 g) and K₃PO₄ (39.6 g) in THF(200 ml) dimethylmalonate (12.85 g) and 1-bromo-3,4-dimethyl-benzene15.0 g) was added under argon. The mixture was refluxed for 16 h, cooledto rt and diluted with EA (300 ml) and filtered. The filtrate wasevaporated and the resulting brown oil was purified on silica geleluting with heptane:EA 4:1 to 1:1 to give2-(3,4-dimethyl-phenyl)-malonic acid dimethyl ester (16.2 g) as acolourless oil which slowly crystallises. ¹H-NMR (300 MHz, CDCl₃):2.25(s, 3H), 2.26(s, 3H), 3.75(s, 6H), 4.59(s, 1H), 7.10–7.20(m, 3H).

b) 2-Phenyl-ethanesulfonic acid[5-(3,4-dimethyl-phenyl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide wasprepared using the above 2-(3,4-dimethyl-phenyl)malonic acid dimethylester in analogy to Referential Example 1. LC-MS: t_(R)=4.61 min,[M+1]⁺=428.19, [M−1]⁻=426.07.

Referential Example 6

a) (In analogy to a procedure given in J. Am. Chem. Soc. 122 (2000),1360–1370.) To a suspension of Pd(OAc)₂ (758 mg),2-(di-tert.-butlylphosphino)-biphenyl (2.02 g) and K₃PO₄ (65.95 g) inTHF (350 ml) dimethylmalonate (21.42 g) and 1-bromo-2,4-dimethyl-benzene(25 g) was added under argon. The mixture was refluxed for 96 h, cooledto rt and diluted with EA (300 ml) and filtered. The filtrate wasevaporated and the resulting brown oil was purified on silica geleluting with heptane:EA 4:1 to 1:1 followed by distillation (bp 95–100°C. at 0.064 mbar) to give 2-(2,4-dimethyl-phenyl)-malonic acid dimethylester (5.66 g) as a colourless oil. ¹H-NMR(300 MHz, CDCl₃): 2.30(s, 6H),3.75(s, 6H), 4.87(s, 1H), 6.98–7.05(m, 2H), 7.25–7.28(m, 1H).

b) 2-Phenyl-ethanesulfonic acid[5-(2,4-dimethyl-phenyl)-6-(2-hydroxy-ethoxy)pyrimidin-4-yl]-amide wasprepared using the above 2-(2,4-dimethyl-phenyl)malonic acid dimethylester in analogy to the procedures given in Referential Example 1.LC-MS: t_(R)=4.54 min, [M+1]⁺=428.23, [M−1]⁻=426.07.

Referential Example 7

a) 2-methoxy-phenol (guaiacol) (48 ml) was slowly added to a stirredsuspension of potassium carbonate (70.8 g) in acetone (480 ml) followedby heating to 45° C. Then dimethylchloromalonate (63.2 ml) in acetone(50 ml) was added within 20 min. The reaction mixture was heated toreflux for 16 h. The solvent was evaporated under reduced pressure, theresidue taken into water and extracted with DCM. The combined organiclayers were dried over sodium sulfate and evaporated. The oily productwas crystallized from methyl-tert.-butyl-ether to givedimethyl-(2-methoxyphenoxy)malonate (86 g).

b) To a stirred solution of sodium methylate (9.7 g) in methanol (100ml) a solution of dimethyl-(2-methoxyphenoxy)malonate (21.7 g) inmethanol (50 ml) was added within 15 min and stirring was continued for30 min followed by the addition of 4-amidino-pyridine hydrochloride (15g, Referential Example 2) followed by stirring at room temperature for20 h. The reaction mixture was concentrated in vacuo. The solid residuewas stirred with diethyl ether. The obtained powder was filtered off anddissolved in water (300 ml). Acetic acid was added to pH=4. Theprecipitated product was filtered off, washed with water and dried invacuo at 500C. 5-(o-methoxyphenoxy)4,6-dihydroxy-2-(4-pyridyl)pyrimidine(20.1 g, possibly also present as the tautomeric5-(2-methoxyphenoxy)-2-(4-pyridyl)-tetrahydropyrimidine-4,6-dion) wasobtained as a white powder.

c) 5-(2-methoxyphenoxy)4,6-dihydroxy-2-(4-pyridyl)-pyrimidine (10 g),N-ethyldiisopropylamine (11.2 g), tetraethylammoniumchloride (11 g) andphosphorus pentachloride (13.8 g) were dissolved in phosphorusoxychloride (25 ml) and heated to reflux for 3 h. The mixture wasevaporated in vacuo, toluene was added and the mixture was againevaporated. The residue was taken into DCM and poured onto ice/water.The layers were separated, the organic layer was washed with water,dried over sodium sulfate and evaporated. After recrystallization fromacetone, pure 4,6-dichloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine(6.52 g) was obtained.

d) A solution of4,6-dichloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (2 g) and2-phenyl-ethanesulfonic acid amide potassium salt (2.82 g, ReferentialExample 1e) in DMF (50 ml) was stirred at rt for 16 h. Bulk of thesolvent was evaporated before it was diluted with diethyl ether (50 ml).The mixture was acidified with 10% aq. citric acid. The precipitate thatformed was collected, washed with diethyl ether (100 ml) and dried togive 2-phenyl-ethanesulfonic acid[6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide(2.23 g) as a beige powder. LC-MS: t_(R)=4.93 min, [M+1]⁺=497.22,[M−1]⁻=494.96.

e) To a suspension of NaH (644 mg, 60% in mineral oil) in DME (15 ml)was added ethylene glycol (15 ml). After evolution of gas had ceased,2-phenyl-ethanesulfonic acid[6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide(800 mg) was added and the resulting solution was stirred at 90° C. for16 h. A further portion of NaH (322 mg) was added and stirring wascontinued at 90° C. for 4 d. The mixture was diluted with EA (200 ml)and washed once with 10% aq. citric acid and 3 times with water. Theorganic phase was evaporated and the residue was suspended in diethylether. The solid material was collected, washed with diethyl ether anddried to give 2-phenyl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide(513 mg) as a beige solid. LC-MS: t_(R)=4.05 min, [M+1]⁺=523.10,[M−1]⁻=521.24.

Referential Example 8

a) 2-Phenylethanesulfonic acid[6-chloro-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-amidewas prepared in analogy to Referential Example 7 from4,6-dichloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine (preparedas disclosed in [6]) and 2-phenylethane sulfonamide potassium salt(Referential Example 1). LC-MS: t_(R)=4.85 min, [M+1]⁺=498.38,[M−1]⁻=496.19.

b) To a suspension of NaH (803 mg 60% dispersion in mineral oil) in DMF(15 ml) was carefully added ethylene glycol (15 ml). After the evolutionof H₂-gas had stopped 2-phenylethanesulfonic acid[6-chloro-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-amide(1 g) was added. The resulting solution was heated to 90° C. and stirredfor 16 h. The pale yellow solution was then cooled to rt, diluted with10% aqueous citric acid solution (100 ml) and extracted three times withEA (50 ml). The combined organic layers were washed once more with 10%aqueous citric acid solution (50 ml) and brine (50 ml) and evaporated.The remaining residue was suspended in water (15 ml). The solid materialwas filtered off, washed with methanol (50 ml) followed by diethyl ether(50 ml) and dried. This gave 2-phenylethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-amide(766 mg) as a white solid. LC-MS: t_(R)=4.32 min, [M+1]⁺=524.47,[M−1]⁻=522.29.

Referential Example 9

2-Phenyl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-pyrazin-2-yl-pyrimidin-4-yl]-amidewas prepared following the procedures given in Referential Example 7starting from 2-amidino-pyrazine hydrochloride. LC-MS: t_(R)=4.37 min,[M+1]⁺=524.18, [M−1]⁻=522.44.

Referential Example 10

2-Phenyl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amidewas prepared following the procedures given in Referential Example 7starting from morpholine-4-carboxamidine hydrobromide. LC-MS: t_(R)=4.75min, [M+1]⁺=531.25, [M−1]⁻=529.50.

Referential Example 11

2-Phenyl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide wasprepared following the procedures given in Referential Example 7starting from formamidine hydrochloride. LC-MS: t_(R)=4.35 min,[M+1]⁺=446.15, [M−1]⁻=444.11.

Referential Example 12

a) To a solution of 3-methoxyphenol (115 g) in acetone (1000 ml) wasadded K₂CO₃ (115 g). The suspension was stirred at 40° C. for 15 min. Asolution of dimethylchloromalonate (133 ml) in acetone was added over aperiod of 45 min. The resulting brown suspension was stirred overnightat 70° C. Finally, the solvent was removed under reduced pressure andthe residue was taken up in water (1000 ml) and extracted twice with DCM(500 ml). The combined organic layers were washed with water (500 ml),dried over Na₂SO₄, and evaporated to give crudedimethyl-(3-methoxyphenoxy)malonate (230 g) as an orange oil. Theproduct was not purified any further.

b) To a solution of dimethyl-(3-methoxyphenoxy)-malonate (11.19 g) inmethanol (100 ml) was added sodium methylate (6.48 g). The yellowsolution was stirred for 6 h at rt. Then, morpholine-4-carboxamidinehydrobromide (8.40 g) was added and the mixture was stirred at rt for 16h. The solvent was removed in vacuo and the residue was dissolved inwater (150 ml) and extracted twice with diethyl ether (150 ml). Theaqueous phase was acidified with 10% aq. citric acid. The solid thatseparated was collected, washed with water, evaporated twice from EA,and dried under high vacuum to give5-(3-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine-4,6-diol (9.66 g) as abeige powder. LC-MS: t_(R)=2.88 min, [M+1]⁺=320.19, [M−1]⁻=318.02.

c) 5-(3-Methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine-4,6-diol (9.66 g)was added portionwise to a mixture of POCl₃ (100 ml) and Hunig's base(50 ml). The black suspension was heated to 110C and stirred for 16 h.The mixture was cooled and N,N-dimethylaniline was added before heatingwas continued for another 24 h. Bulk of the solvents was evaporated andthe remaining oil was poured into water. The dark solution was treatedwith charcoal before it was extracted twice with EA (300 ml). Theorganic phase was washed with brine and water, dried over MgSO₄ andevaporated. The remaining oil was chromatographed on silica gel elutingwith heptane:EA. The product was recrystallised from 2-propanol, thepale yellow crystals were washed with diethyl ether to give4-[4,6-dichloro-5-(3-methoxy-phenoxy)-pyrimidin-2-yl]-morpholine (7.48g). LC-MS: t_(R)=5.56 min, [M+1]⁺=355.99.

d) A solution of4-[4,6-dichloro-5-(3-methoxy-phenoxy)-pyrimidin-2-yl]-morpholine (1.0 g)and 2-phenyl-ethanesulfonic acid amide potassium salt (1.57 g,Referential Example 1e) in DMSO (15 ml) was stirred at 60° C. for 24 h.The solution was diluted with water (75 ml) and extracted twice withdiethyl ether (75 ml) before it was acidified with 10% aq. citric acid.The mixture was extracted twice with EA (150 ml). The organic phase waswashed with water (50 ml). The product precipitated upon evaporation ofthe solvent. The solid was collected, washed with diethyl ether anddried to give 2-phenyl-ethanesulfonic acid[6-chloro-5-(3-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide(1.28 g) as off-white powder. LC-MS: t_(R)=5.34 min, [M+1]⁺=505.12,[M−1]⁻=502.97.

e) A suspension of 2-phenyl-ethanesulfonic acid[6-chloro-5-(3-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide(1.27 g) in ethylene glycol (12 ml) was treated with K-tert.-butylate(2.82 g). The resulting solution was stirred at 100° C. for 12 d. Thesolution was cooled to rt, diluted with 10% aq. citric acid (150 ml) andextracted twice with EA (150 ml). The organic phase was washed withwater (50 ml) and evaporated. The crude product was purified bychromatography on silica gel eluting with heptane:EA 1:1 to 1:2 tofurnish 2phenyl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide(1.1 g) as a white solid. LC-MS: t_(R)=4.66 min, [M+1]⁺=531.20,[M−1]⁻=529.14.

Referential Example 13

2-Phenyl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-pyrimidin-4-yl]-amide wasprepared following the procedures given in Referential Example 12starting from formamidine hydrochloride. ¹H-NMR (300 MHz, CDCl₃):3.14–3.21(m, 2H), 3.70–3.74(m, 2H), 3.79(s, 3H), 3.94–4.01(m, 2H),4.40–4.46 (m, 2H), 6.41(dd, J=2.4, 8.4, 1H), 6.47(t, J=2.4, 1H),6.66(dd, J=1.8, 8.4, 1H), 7.16–7.32(m, 6H), 8.37(s, 1H); LC-MS:t_(R)=4.33 min, [M+1]⁺=446.27, [M−1]⁻=444.05.

Referential Example 14

a) 2-Thiophen-2-yl-ethanesulfonyl chloride was obtained starting fromcommercial 2-(2-bromo-ethyl)-thiophene following the procedures given inthe literature (J. Am. Chem. Soc. 103 (1981),1525–1533).

b) A solution of crude 2-thiophen-2-yl-ethanesulfonyl chloride (25 g) inTHF (400 ml) was treated with sat. aq. ammonia (60 ml) at 0° C. Themixture was stirred at rt for 16 h before it was neutralised with 25%aq. HCl (60 ml). Bulk of the THF was evaporated. The aq. solution wasextracted twice with EA. The organic phase was washed with water andevaporated. The remaining oil was purified by chromatography on silicagel eluting with heptane:EA 1:1. The product was further purified byrecrystallisation from diethyl ether/pentane to give2-thiophen-2-yl-ethanesulfonic acid amide (8.46 g) as off-whitecrystals. ¹H-NMR (300 MHz, CDCl₃): 3.36–3.50(m, 4H), 4.54(s br, 2H),6.89–6.92(m, 1H), 6.95(dd, J=3.5, 5.1, 1H), 7.20(dd, J=1.1, 5.0, 1H).

c) A solution of 2-thiophen-2-yl-ethanesulfonic acid amide (3.77 g) inmethanol (200 ml) was treated with K-tert.-butylate (2.21 g), stirred atrt for 15 min, evaporated and dried under high vacuum to give2-thiophen-2-yl-ethanesulfonic acid amide potassium salt (4.5 g) as abeige powder.

d) 2-Thiophen-2-yl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide was prepared usingthe above 2-thiophen-2-yl-ethanesulfonic acid amide potassium saltfollowing the procedures given in Referential Example 1. ¹H-NMR(300 MHz,CDCl₃): 2.42(s, 3H), 3.33–3.41(m, 2H), 3.81–3.86(m, 2H), 3.994.07(m,2H), 4.46–4.51(m, 2H), 6.82–6.86(m, 1H), 6.92(dd, J=3.5, 5.1, 1H),7.13–7.18(m, 3H), 7.28–7.32(m 2H), 8.51(s, 1H); LC-MS: t_(R)=4.18 min,[M+1]⁺=420.24, [M−1]⁻=418.20.

Referential Example 15

a) At 35° C. a solution of 4-chlorophenylacetic acid methyl ester (52 g)in THF (170 ml) was carefully added over a period of 70 min to asuspension of NaH (15.6 g) in dry THF (550 ml). Stirring was continuedfor 40 min without heating and the temperature dropped to 290C. Theevolution of gas had stopped before dimethylcarbonate (94.8 ml) wasadded dropwise while the temperature of the mixture was maintained at25–28° C. After the evolution of gas had ceased, the mixture was dilutedwith THF (200 ml) and stirring was continued for 72 h at rt. The mixturewas carefully acidified with aq. HCl before bulk of the THF was removedin vacuo. The residue was dissolved in diethyl ether (1200 ml), washedthree times with 1 N aq. HCl and once with brine, dried over MgSO₄ andevaporated. The residue formed was collected, washed with diethyl etherand dried to give 2-(4-chloro-phenyl)-malonic acid dimethyl ester (42 g)as white crystals.

b) A solution of 2-(4-chlorophenyl)-malonic acid dimethyl ester (18.90g) in methanol (200 ml) was added dropwise at 0° C. to a solution sodiummethylate (14.60 g) in methanol (150 ml). The mixture was stirred for 1h at 0° C. before formamidine hydrochloride (7.66 g) was added. Thesuspension was stirred at rt for 20 h. The solvent was removed and theresidue was suspended in 2 N aq. HCl (200 ml). The pH of the suspensionwas carefully adjusted to 4–5 by adding 10 M NaOH (20 ml), stirring wascontinued for 30 min. The white precipitate was collected, washed withwater and diethyl ether and dried to give5-(4-chlorophenyl)-pyrimidine-4,6-diol (16.44 g) as a white powder.LC-MS: t_(R)=2.75 min, [M+H]+=222.96, [M−H]⁻=220.92.

c) To a suspension of 5-(4-chlorophenyl)-pyrimidine-4,6-diol (16.44 g)in POCl₃ (165 ml) was carefully added N,N-dimethylaniline (16.5 ml). Themixture was refluxed for 1.5 h. The dark green solution was evaporatedand the residue was poured onto ice/water. The suspension was dilutedwith 2 N HCl (200 ml) and water (800 ml) and stirred at 2°C. for 1 h.The precipitate was collected, washed with water and dried to give4,6-dichloro-5-(4-chlorophenyl)-pyrimidine (18.66 g) as a slightly greenpowder.

d) A solution of 4,6-dichloro-5-(4-chlorophenyl)pyrimidine (848 mg),2-thiophen-2-yl-ethanesulfonic acid amide potassium salt (1.5 g,Referential Example 14) and Hunig's base (1 ml) in DMSO (20 ml) wasstirred at rt for 24 h before it was diluted with water (200 ml) andextracted twice with diethyl ether. The aqueous layer was acidified withacetic acid. The precipitate was collected, washed with water anddiethyl ether and dried to give 2-thiophen-2-yl-ethanesulfonic acid[6-chloro-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide (930 mg) as a beigepowder. LC-MS: t_(R)=5.01 min, [M+1]⁺=413.49, [M−1]⁻=411.93.

e) 2-Thiophen-2-yl-ethanesulfonic acid[6-chloro-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide (930 mg) was addedto a solution of K-tert. butylate (1.16 g) in ethylene glycol (10 ml).The mixture was stirred at 110° C. for 12 h before it was diluted withwater (150 ml), acidified with 10% aq. citric acid (13 ml). Theresulting precipitate was collected, washed with water and diethyl etherand dried to give (820 mg) 2-thiophen-2-yl-ethanesulfonic acid[5-(4-chloro-phenyl)-6-(2-hydroxy-ethoxy) -pyrimidin-4-yl]-amide as abeige powder. LC-MS: t_(R)=4.43 min, [M+1]⁺=440.01, [M−1]⁻=437.99.

Referential Example 16

2-Thiophen-2-yl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amidewas prepared following the procedures given in Referential Example 7using 2-thiophen-2-yl-ethanesulfonic acid amide potassium salt(Referential Example 14).; LC-MS: t_(R)=4.00 min, [M+1]⁺=529.29,[M−1]⁻=526.97.

Referential Example 17

2-Thiophen-2-yl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amidewas prepared following the procedures given in Referential Example 10using 2-thiophen-2-yl-ethanesulfonic acid amide potassium salt(Referential Example 14).; LC-MS: t_(R)=4.62 min, [M+1]⁺=537.21,[M−1]⁻=534.96.

Referential Example 18

a) 2-Pyridin-2-yl-ethanesulfonyl chloride hydrochloride was preparedstarting from commercial 2-pyridine-2-ethane sulfonic acid following theprocedure given in J. Med. Chem. 36 (1993), 320–330.

b) 2-Pyridin-2-yl-ethanesulfonic acid amide potassium salt was preparedusing the above 2-pyridin-2-yl-ethanesulfonyl chloride hydrochloridefollowing the procedures given in Referential Example 14 b and 14c.

c) A solution of4,6-dichloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (1.75 g,Referential Example 7) and 2-pyridin-2-yl-ethanesulfonic acid amidepotassium salt (1.13 g) in DMSO (30 ml) was stirred at rt for 24 h.Triethylamine (657 mg) was added and stirring was continued for another96 h before the mixture was diluted with ethyl acetate (150 ml) andwashed 4% aq. citric acid and water. The aqueous phase was extractedthree more times with EA. The organic phase was dried over MgSO₄ andevaporated. The crude product was purified by column chromatography onsilica gel eluting with EA containing 0–10% methanol to give2-pyridin-2-yl-ethanesulfonic acid[6-chloro-5-(2-methoxyphenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide (950mg) as a brown powder. LC-MS: t_(R)=3.63 min, [M+1]⁺=498.31,[M−1]⁻=496.10.

d) To a suspension of NaH (701 mg, 60% in mineral oil) in DMF (15 ml)was added ethylene glycol (15 ml). After the evolution of gas hadceased, 2-pyridin-2-yl-ethanesulfonic acid[6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide(800 mg) was added and the resulting solution was stirred at 90° C. for40 h. The solution was neutralised with 2 N aq. HCl (7 ml) before it wasevaporated. The brown residue was purified by chromatography on prep.tlc-plates with EA:methanol:sat. aq. ammonia 10:2:1. The product wasfurther purified by crystallisation from methanol:diethyl ether:pentaneto give 2-pyridin-2-yl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide(280 mg) as beige crystals. ¹H-NMR(300 MHz, CDC₃): 3.36–3.43(m, 2H),3.86–3.90(m, 2H), 3.94(s, 3H), 4.23–4.30(m, 2H), 4.564.62(m, 2H),6.91(dt, Jd=1.5, Jt=7.7, 1H, 7.00(dd, J=1.7, 8.2, 1H, 7.08–7.20(m, 4H),7.57(dt, Jd=1.8, Jt=7.9, 1H), 8.15(dd, J=1.7, 4.6, 2H), 8.43(d, J=4.4,1H), 8.72(dd, J=1.7, 4.6, 2H); LC-MS: t_(R)=3.23 min, [M+1]⁺=524.48,[M−1]⁻=522.25.

Referential Example 19

a) Phenyl-methanesulfonamide potassium salt was prepared in analogy tothe procedures given in Referential Example 1d and 1e using commercialphenyl-methanesulfonyl chloride. ¹H-NMR(300 MHz, DSMO): 3.73(s, 2H),7.13–7.30(m, 5H).

b)N-[6-(2-Hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-C-phenyl-methanesulfonamidewas prepared in analogy to Referential Example 7 using the abovephenyl-methanesulfonamide potassium salt. LC-MS: t_(R)=3.99 min,[M+1]⁺=509.32, [M−1]⁻=507.31.

Referential Example 20

N-[6-(2-Hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-C-phenyl-methanesulfonamide was prepared in analogy to Referential Example 8using phenyl-methanesulfonamide potassium salt (Referential Example 19).LC-MS: t_(R)=4.15 min, [M+1]⁺=510.34, [M−1]⁻=508.54.

Referential Example 21

N-[6-(2-Hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-C-phenyl-methanesulfonamidewas prepared in analogy to Referential Example 10 usingphenyl-methanesulfonamide potassium salt (Referential Example 19).LC-MS: t_(R)=4.54 min, [M+1]⁺=517.32, [M−1]⁻=515.07.

Referential Example 22

a) p-Tolyl-methanesulfonyl chloride was prepared by oxidisingcommercially available p-tolyl-methanethiol with N-chlorosuccinimide inanalogy to the procedure disclosed in [9].

b) p-Tolyl-methanesulfonamide potassium salt was prepared in analogy tothe procedures given in Referential Example 1d and 1e. ¹H-NMR(300 MHz,CDCl₃) (sulfonamide): 2.36(s, 3H), 4.27(s, 2H), 4.63(s br, 2H), 7.20(d,J=7.9, 2H), 7.30(d, J=8.1, 2H).

c)N-[6-(2-Hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-C-p-tolyl-methanesulfonamidewas prepared using the above p-tolyl-methanesulfonamide potassium saltin analogy to the procedures given in Referential Example 7. LC-MS:t_(R)=4.18 min, [M+1]⁺=523.22, [M−1]⁻=521.19.

Referential Example 23

N-[6-(2-Hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-pyrazin-2-yl-pyrimidin-4-yl]-C-p-tolyl-methanesulfonamide was prepared using the abovep-tolyl-methanesulfonamide potassium salt in analogy to the proceduresgiven in Referential Example 9. LC-MS: t_(R)=4.46 min, [M+1]⁺=524.20,[M−1]⁻=521.93.

Referential Example 24

a) 3-Phenyl-propane-1-sulfonyl chloride was prepared by oxidisingcommercially available 3-phenyl-propane-1-thiol with N-chlorosuccinimidein analogy to the procedure disclosed in [9].

b) 3-Phenyl-propane-1-sulfonic acid amide potassium salt was prepared inanalogy to the procedures given in Referential Example 1d and 1e. ¹H-NMR(300 MHz, CDCl₃) (sulfonamide): 2.11–2.23(m, 2H), 2.76(t, J=7.5, 2H),3.05–3.13(m, 2H), 4.85(s br, 2H), 7.14–7.40(m, 5H).

c) 3-Phenyl-propane-1-sulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide was prepared inanalogy to the procedures given in Referential Example 1 using the above3-phenyl-propane-1-sulfonic acid amide potassium salt. LC-MS: t_(R)=4.66min, [M+1]⁺=428.24, [M−1]⁻=426.21.

Referential Example 25

3-Phenyl-propane-1-sulfonic acid[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimid-4yl]-amidewas prepared in analogy to the procedures given in Referential Example 7using 3-phenyl-propane-1-sulfonic acid amide potassium salt ofReferential Example 24. LC-MS: t_(R)=4.14 min, [M+1]⁺=537.45,[M−1]⁻=535.41.

Referential Example 26

3-Phenyl-propane-1-sulfonic acid[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2]bipyrimidinyl-4-yl]-amidewas prepared in analogy to the procedures given in Referential Example 8using 3-phenyl-propane-1-sulfonic acid amide potassium salt ofReferential Example 24. LC-MS: t_(R)=4.37 min, [M+1]⁺=538.38,[M−1]⁻=536.27.

Referential Example 27

3-Phenyl-propane-1-sulfonic acid[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amidewas prepared in analogy to the procedures given in Referential Example10 using 3-phenyl-propane-1-sulfonic acid amide potassium salt ofReferential Example 24. LC-MS: t_(R)=4.80 min, [M+1]⁺=545.40,[M−1]⁻=543.52.

Referential Example 28

N-[6-(3-Hydroxy-propoxy-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-C-phenyl-methanesulfonamidewas prepared in analogy to the procedures given in Referential Example20 using propane-1,3-diol instead of ethylene glycol. LC-MS: t_(R)=4.13min, [M+1]⁺=524.34, [M−1]⁻=522.19.

Referential Example 29

3-Phenyl-propane-1-sulfonic acid[6-(3-hydroxy-propoxy)-5-p-tolyl-pyrimidin-4-yl]-amide was prepared inanalogy to the procedures given in Referential Example 24 usingpropane-1,3-diol instead of ethylene glycol. LC-MS: t_(R)=4.72 min,[M+1]⁺=442.28, [M−1]⁻=440.22.

EXAMPLES

The following examples illustrate the invention but do not at all limitthe scope thereof.

The following reagents have been synthesised in order to prepare theexamples listed below according to or in analogy to literatureprocedures: 5-bromo-2-chloro-pyrimidine (Aust. J. Chem. 17 (1964),794–802; J. Org. Chem. 25 (1960), 1916–1919); 2,5-dichloro-pyrimidine(in analogy to 5-bromo-2-chloro-pyrimidine using chlorine instead ofbromine); 2-chloro-5-methyl-pyrimidine (J. Med. Chem. 6 (1963), 697–701;Aust. J. Chem. 30 (1977), 2515–2525);2-methanesulfonyl-5-methoxy-pyrimidine (J. Chem. Soc. Perkin Trans. 1,1999, 3265–3268; J. Org. Chem. 27 (1962), 3614–3617);2-chloro-5-methylsulfanyl-pyrimidine (II Farmaco 43 (1988), 277–292;French Patent 1 549 494 (1968));2-methanesulfonyl-5-trifluoromethyl-pyrimidine (Tetrahedron Lett. 37(1996), 1829–1832); 2-methanesulfonyl-4,6-dimethoxy-pyrimidine wasprepared starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine usingstandard methodology.

All other reagents constitute commercially available ingredients.

Example 1

To sodium hydride (50 mg, 60% in mineral oil) was added THF (25 ml)followed by 2-phenyl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (150 mg,Referential Example 1). The mixture was stirred for 1 h at rt before2-chloro-pyrimidine (86 mg) was added. Stirring was continued for 17 hat 80° C. The solvent was evaporated and diethylether (20 ml) was addedto the residue. The precipitate was filtered off and washed withdiethylether, dissolved in water (20 ml) and acidified with citric acidand extracted twice with EA (50 ml). The organic phase was washed withwater, dried over Na₂SO₄ and evaporated. The residue is suspended in2-propanol (15 ml) and stirred at 70° C. for 10 min and cooled to 0° C.before the solid material is collected, washed with 2-propanol (2 ml)and dried under high vacuum to furnish 2-phenyl-ethanesulfonic acid{6-[2-(pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (133mg) as a white powder. LC-MS: t_(R)=4.97 min, [M+1]⁺=492.34,[M−1]⁻=490.28.

Example 2

To sodium hydride (27 mg, 60% in mineral oil) was added THF (15 ml)followed by 2-phenyl-ethanesulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (80 mg,Referential Example 1). The mixture was stirred for 1 h at rt before2-chloro-5-trifluoromethyl-pyridine (86 mg) was added. Stirring wascontinued for 17 h at 80° C. The solvent was evaporated, the residue wasdissolved in water (20 ml), acidified with citric acid. The suspensionwas treated with hexane (15 ml). The solid material was collected,washed with hexane:EA 1:1 (20 ml) and dried to yield2-phenyl-ethanesulfonic acid{5-p-tolyl-6-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide(96 mg) as beige powder. LC-MS: t_(R)=5.86 min, [M+1]⁺=559.20,[M−1]⁻=557.37.

Example 3

To a suspension of NaH (17 mg, 60% in mineral oil) in DME (5 ml) wasadded 2-(4-bromo-phenoxy)-ethanol (111 mg). The mixture was stirred at50° C. for 1 h before 2-phenyl-ethanesulfonic acid(6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (100 mg, Referential Example1f) and K-tert.-butylate (25 mg) was added. The mixture was stirred at70° C. for 16 h. A further portion of K-tert.-butylate (50 mg) was addedand stirring was continued at 70° C. for 12 h and at rt for 72 h. Thesolvent was evaporated. The residue was treated with water (40 ml),acidified with 10% aq. citric acid and extracted twice with EA (50 ml).The organic phase was washed with water and evaporated. The crudeproduct was crystallised from 2-propanol to give 2-phenyl-ethanesulfonicacid {6-[2-(4-bromo-phenoxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide(127 mg) as a beige powder. LC-MS: t_(R)=6.14 min, [M+1]⁺=568.38,[M−1]⁻=570.15.

Example 4

To a suspension of NaH (29 mg 60% dispersion in mineral oil) in amixture of DMF and THF (2.5 ml each) was added 2-phenylethanesulfonicacid[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-amide(150 mg). After gas-evolution had ceased, 2-chloropyrimidine (82 mg) wasadded. The resulting pale yellow suspension was stirred at 70° C. for 4h. It was cooled to rt, diluted with EA (75 ml) and washed with 10%aqueous citric acid solution (50 ml) followed by water (50 ml). Theorganic layer was evaporated and the remaining residue was purified onprep. tlc plates (silica gel, 0.5 mm layer thickness) developing withEA:methanol:sat. aqueous ammonia 8:2:1. This furnished2-phenylethanesulfonic acid{5-(2-methoxy-phenoxy)-6-[2-(pyrimidin-2-yloxy)-ethoxy]-2-(2-pyrimidinyl)-4-pyrimidinyl}-amideas a pale yellow powder. LC-MS: t_(R)=4.60 min, [M+1]⁺=602.69,[M−1]⁻=600.43.

Example 5

To a suspension of NaH (29 mg 60% dispersion in mineral oil) in amixture of DMF and THF (2.5 ml each) was added 2-phenylethanesulfonicacid[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-amide(150 mg). After gas-evolution had ceased, 2-chloro-5-bromopyrimidine(138 mg) was added. The resulting orange suspension was stirred at 700Cfor 4 h. A further portion of NaH (29 mg 60% dispersion in mineral oil)followed by 2-chloro-5-bromopyrimidine (138 mg) was added. Heating andstirring was continued for 25 h. Eventually, the reaction mixture wascooled to rt, diluted with EA (75 ml) and washed with 10% aqueous citricacid solution (50 ml) followed by water (50 ml). The organic layer wasevaporated and the remaining residue was purified on prep. tlc plates(silica gel, 0.5 mm layer thickness) developing with EA:methanol:sat.aqueous ammonia 8:2:1. This furnished 2phenylethanesulfonic acid{5-(2-methoxy-phenoxy)-6-[2-(5-bromopyrimidin-2-yloxy)-ethoxy]-2-(2-pyrimidinyl)-4-pyrimidinyl}-amideas a pale yellow powder. LC-MS: t_(R)=5.11 min, [M+1]⁺=680.23,[M−1]⁻=678.36.

Example 6

To a suspension of NaH (29 mg, 60% dispersion in mineral oil) in amixture of DMF and THF (2.5 ml each) was added 2-phenylethanesulfonicacid[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-amide(150 mg). After gas-evolution had ceased,4,6-dimethoxy-2-methylsulfonylpyrimidine (156 mg) was added. Theresulting yellow suspension was stirred at 70° C. for 4 h. Eventually,the reaction mixture was cooled to rt, diluted with EA (75 ml) andwashed with 10% aqueous citric acid solution (50 ml) followed by water(50 ml). The organic layer was evaporated and the remaining residue waspurified on prep. tlc plates (silica gel, 0.5 mm layer thickness)developing with EA:methanol:sat. aqueous ammonia 8:2:1. This furnished2-phenylethanesulfonic acid{5-(2-methoxy-phenoxy)-6-[2-(4,6-dimethoxy-pyrimidin-2-yloxy)-ethoxy]-2-(2-pyrimidinyl)-4-pyrimidinyl}-amideas a pale yellow powder. LC-MS: t_(R)=5.21 min, [M+1]⁺=662.69,[M−1]⁻=660.23.

Example 7–86

The Examples represented in Table 1 to Table 8 have been prepared inanalogy to the Examples 1 to 6 using the Referential Examples 1 to 29 asstarting materials.

TABLE 1

Ex. No Ref. Ex. No R¹ R² R³ LC-MS 7 1

H

t_(R) = 5.41 min[M + H]⁺: 570.22[M − H]⁻: 568.16 8 1

H

t_(R) = 5.11 min[M + H]⁺: —[M − H]⁻: 504.11 9 2

t_(R) = 5.26 min[M + H]⁺: 530.32[M − H]⁻: — 10 2

t_(R) = 5.21 min[M + H]⁺: 647.10[M − H]⁻: 646.54 11 2

t_(R) = 4.84 min[M + H]⁺: 583.22[M − H]⁻: 581.18 12 2

t_(R) = 4.82 min[M + H]⁺: 599.34[M − H]⁻: 597.45 13 3

t_(R) = 5.28 min[M + H]⁺: 604.11[M − H]⁻: 602.42 14 3

t_(R) = 5.33 min[M + H]⁺: 647.96[M − H + 2]⁻: 647.52 15 3

t_(R) = 4.97 min[M + H]⁺: 600.19[M − H]⁻: 598.28 16 4

H

t_(R) = 5.51 min[M + H]⁺: 589.97[M − H]⁻: 587.47 17 4

H

t_(R) = 5.56 min[M + 2 + H]⁺: 636.23[M − H]⁻: 632.12 18 4

H

t_(R) = 5.18 min[M + H + 2]⁺: 587.88[M − H]⁻: 583.91 19 5

H

t_(R) = 5.59 min[M + H]⁺: 584.10[M − H + 2]⁻: 583.54 20 5

H

t_(R) = 5.24 min[M + H]⁺: 536.32[M − H]⁻: 534.40 21 6

H

t_(R) = 5.55 min[M + H]⁺: 584.18[M − H]⁻: 582.12 22 6

H

t_(R) = 5.46 min[M + H]⁺: 552.03[M − H]⁻: 550.15 23 7

t_(R) = 4.47 min[M + H]⁺: 600.95[M − H]⁻: 598.84 24 7

t_(R) = 4.97 min[M + H]⁺: 635.16[M − H]⁻: 632.99 25 7

t_(R) = 5.02 min[M + H]⁺: 679.17[M − H]⁻: — 26 7

t_(R) = 4.68 min[M + H]⁺: 631.30[M − H]⁻: 629.22 27 8

t_(R) = 4.90 min[M + H]⁺: 636.17[M − H]⁻: 634.43 28 8

t_(R) = 4.73 min[M + H]⁺: 614.10[M − H]⁻: 612.15 29 8

t_(R) = 4.68 min[M + H]⁺: 632.33[M − H]⁻: 630.00 30 8

t_(R) = 5.08 min[M + H]⁺: 670.19[M − H]⁻: 668.34 31 8

t_(R) = 5.42 min[M + H]⁺: 669.05[M − H]⁻: 666.80 32 9

t_(R) = 4.70 min[M + H]⁺: 602.25[M − H]⁻: 600.18 33 9

t_(R) = 5.19 min[M + H + 2]⁺: 681.96[M − H]⁻: 678.21 34 9

t_(R) = 4.88 min[M + H]⁺: 632.24[M − H]⁻: 630.35 35 9

t_(R) = 5.11 min[M + H]⁺: 648.57[M − H]⁻: 646.11 36 10

t_(R) = 5.13 min[M + H]⁺: 609.31[M − H]⁻: 607.25 37 10

t_(R) = 5.67 min[M + H]⁺: 686.92[M − H]⁻: 685.02 38 10

t_(R) = 5.30 min[M + H]⁺: 639.30[M − H]⁻: 637.13 39 10

t_(R) = 5.51 min[M + H]⁺: 654.92[M − H]⁻: 653.08 40 11

H

t_(R) = 4.84 min[M + Na]⁺: 524.32[M − H]⁻: 522.00 41 11

H

t_(R) = 5.38 min[M + H]⁺: 601.95[M − H]⁻: 600.33 42 11

H

t_(R) = 5.01 min[M + H]⁺: 554.14[M − H]⁻: 552.03 43 11

H

t_(R) = 5.75 min[M + H]⁺: 591.44[M − H]⁻: 588.99 44 12

t_(R) = 5.52 min[M + H]⁺: 687.24[M − H]⁻: 685.44 45 12

t_(R) = 5.18 min[M + H]⁺: 639.32[M − H]⁻: 637.14 46 13

H

t_(R) = 5.25 min[M + H]⁺: 602.00[M − H]⁻: 599.99 47 13

H

t_(R) = 4.89 min[M + H]⁺: 553.98[M − H]⁻: 551.97

TABLE 2

Ex. No Ref. Ex. No R¹ R² R³ LC-MS 48 14

H

t_(R) = 5.24 min[M + H]⁺: 532.13[M − H]⁻: 530.35 49 14

H

t_(R) = 5.31 min[M + H]⁺: 576.07[M − H]⁻: 574.19 50 14

H

t_(R) = 4.95 min[M + H]⁺: 528.17[M − H]⁻: 526.12 51 15

H

t_(R) = 5.28 min[M + H]⁺: 552.39[M − H]⁻: 550.27 52 15

H

t_(R) = 5.33 min[M + H + 2]⁺: 598.29[M − H]⁻: 595.43 53 15

H

t_(R) = 5.07 min[M + H]⁺: 532.29[M − H]⁻: 529.95 54 15

H

t_(R) = 4.99 min[M + H]⁺: 547.89[M − H]⁻: 545.91 55 16

t_(R) = 5.07 min[M + H]⁺: 641.16[M − H]⁻: 638.75 56 16

t_(R) = 4.96 min[M + H]⁺: 685.12[M − H]⁻: 683.33 57 16

t_(R) = 4.62 min[M + H]⁺: 637.18[M − H]⁻: 635.04 58 17

t_(R) = 5.56 min[M + H]⁺: 693.12[M − H]⁻: 691.31 59 17

t_(R) = 5.21 min[M + H]⁺: 645.35[M − H]⁻: 643.48

TABLE 3

Ex. No Ref. Ex. No R¹ R² R³ LC-MS 60 18

t_(R) = 3.56 min[M + H]⁺: 602.40[M − H]⁻: 600.14 61 18

t_(R) = 4.14 min[M + H + 2]⁺: 682.26[M − H]⁻: 678.23

TABLE 4

Ex. No Ref. Ex. No R¹ R² R³ LC-MS 62 19

t_(R) = 4.46 min[M + H]⁺: 587.43[M − H]⁻: 585.40 63 19

t_(R) = 5.00 min[M + H + 2]⁺: 667.12[M − H + 2]⁻: 665.47 64 19

t_(R) = 5.71 min[M + H + 2]⁺: 665.39[M − H + 2]⁻: 662.71 65 20

t_(R) = 4.43 min[M + H]⁺: 588.66[M − H]⁻: 586.33 66 20

t_(R) = 4.93 min[M + H + 2]⁺: 668.21[M − H + 2]⁻: 665.81 67 20

t_(R) = 5.52 min[M + H + 2]⁺: 666.29[M − H]⁻: 662.25 68 21

t_(R) = 5.01 min[M + H]⁺: 595.27[M − H]⁻: 593.18 69 21

t_(R) = 5.46 min[M + H]⁺: 673.11[M − H + 2]⁻: 673.42

TABLE 5

Ex. No Ref. Ex. No R¹ R² R³ LC-MS 70 22

t_(R) = 4.58 min[M + H]⁺: 601.39[M − H]⁻: 599.12 71 22

t_(R) = 5.28 min[M + H + 2]⁺: 681.24[M − H]⁻: 677.00 72 23

t_(R) = 4.76 min[M + H]⁺: 602.20[M − H]⁻: 600.18 73 23

t_(R) = 5.24 min[M + H]⁺: 680.13[M − H]⁻: 678.14

TABLE 6

Ex. No Ref. Ex. No R¹ R² R³ LC-MS 74 24

H

t_(R) = 5.13 min[M + H]⁺: 506.25[M − H]⁻: 504.26 75 24

H

t_(R) = 5.62 min[M + H + 2]⁺: 586.33[M − H]⁻: 582.11 76 25

t_(R) = 4.56 min[M + H]⁺: 615.53[M − H]⁻: 613.40 77 25

t_(R) = 5.09 min[M + H]⁺: 693.22[M − H]⁻: 691.07 78 26

t_(R) = 4.58 min[M + H]⁺: 616.54[M − H]⁻: 614.29 79 26

t_(R) = 5.09 min[M + H]⁺: 694.42[M − H]⁻: 692.21 80 27

t_(R) = 5.20 min[M + H]⁺: 623.37[M − H]⁻: 621.19 81 27

t_(R) = 5.66 min[M + H + 2]⁺: 703.51[M − H + 2]⁻: 701.52

TABLE 7

Ex. No Ref. Ex. No R¹ R² R³ LC-MS 82 28

t_(R) = 4.55 min[M + H]⁺: 602.43[M − H]⁻: 600.26 83 28

t_(R) = 5.59 min[M + H]⁺: 669.49[M − H]⁻: 667.40

TABLE 8

Ex. No Ref. Ex. No R¹ R² R³ LC-MS 84 29

H

t_(R) = 5.71 min[M + H + 2]⁺: 600.18[M − H]⁻: 596.05 85 29

H

t_(R) = 6.21 min[M + H + 2]⁺: 598.96[M − H]⁻: 594.67 86 29

H

t_(R) = 6.16 min[M + H ]⁺: 587.19[M − H]⁻: 584.74

1. A compound of the formula I

wherein R¹ and R² represent aryl or heteroaryl; R³ represents phenyl;mono-, di- or tri-substituted phenyl substituted with substituentsselected from the group consisting of lower alkyl, lower alkenyl, loweralkynyl, phenyl, lower alkoxy, amino, lower alkylamino, amino-loweralkyl, trifluoromethyl, trifluoromethoxy, halogen, lower alkylthio,hydroxy, hydroxy-lower alkyl, cyano, carboxyl, lower alkanoyl andformyl; benzofuranyl; or heteroaryl; R⁴ represents hydrogen; halogen;trifluoromethyl; lower alkyl; lower alkyl-amino; lower alkoxy; loweralkyl-sulfono; lower alkyl-sulfinyl; lower alkylthio; loweralkylthio-lower alkyl; hydroxy-lower alkyl; lower alkyl-oxy-lower alkyl;hydroxy-lower alkyl-oxy-lower alkyl; hydroxy-lower alkyl-amino; loweralkyl-amino-lower alkyl; amino; di-lower alkyl-amino; [N-(hydroxy-loweralkyl)-N-(lower alkyl)]-amino; aryl; aryl-amino; aryl-lower alkyl-amino;aryl-thio; aryl-lower alkyl-thio; aryloxy; aryl-lower alkyl-oxy;aryl-lower alkyl; aryl-sulfinyl; heteroaryl; heteroaryl-oxy; heteroaryl-lower alkyl-oxy; heteroaryl-amino; heteroaryl-lower alkyl-amino;heteroaryl-thio; heteroaryl-lower alkyl-thio; heteroaryl-lower alkyl;heteroaryl-sulfinyl; heterocyclyl; heterocyclyl-lower alkyl-oxy;heterocyclyl-oxy; heterocyclyl-amino; heterocyclyl-lower alkyl-amino;heterocyclyl-thio; heterocyclyl-lower alkyl-thio; heterocyclyl-loweralkyl; heterocyclyl-sulfinyl; cycloalkyl; cycloalkyl-oxy;cycloalkyl-lower alkyl-oxy; cycloalkyl-amino; cycloalkyl-loweralkyl-amino; cycloalkyl-thio; cycloalkyl-lower alkyl-thio;cycloalkyl-lower alkyl; or cycloalkyl-sulfinyl; X represents oxygen;sulfur; NH; CH₂ or a bond; Y represents oxygen; sulfur or —NH—; Zrepresents oxygen; sulfur, —NH— or a bond; Q represents —(CH₂)_(k)—;—(CH₂)_(m)—C≡C—(CH₂)_(p)—, in case p represents 0 (zero), Z represents abond; or —CH₂-cyclopropylen-CH₂—; k represents the numbers 2, 3, 4, 5,or 6; m represents the numbers 1, 2, or 3; p represents the numbers 0,1, 2 or 3; n represents the numbers 1, 2, or 3; or pure diastereomers,mixtures of diastereomers, diastereomeric racemates, mixtures ofdiastereomeric racemates, the meso-forms or pharmaceutically acceptablesalts thereof.
 2. The compound of claim 1, wherein R¹, R², R⁴, Q, Y, Zand n are as defined in claim 1, X, represents oxygen and R³ representsphenyl or mono-substituted phenyl substituted with halogen, lower alkyl,lower alkenyl, lower alkoxy, amino, lower alkyl-amino, lower alkyl-thio,hydroxy, hydroxymethyl or lower alkanoyl; or pharmaceutically acceptablesalts thereof.
 3. The compound of claim 1, wherein R¹, R², R⁴, Q, and nare as defined in claim 1, X, Y and Z represent oxygen and R³ representsphenyl or mono-substituted phenyl substituted with halogen, lower alkyl,lower alkenyl, lower alkoxy, amino, lower alkyl-amino, lower alkyl-thio,hydroxy, hydroxymethyl or lower alkanoyl; or pharmaceutically acceptablesalts thereof.
 4. The compound of claim 1, wherein R¹, R², R⁴, and n areas defined in claim 1, X, Y and Z represent oxygen, Q represents—(CH₂)_(k)— with k=2 or 3 and R³ represents phenyl or mono-substitutedphenyl substituted with halogen, lower alkyl, lower alkenyl, loweralkoxy, amino, lower alkyl-amino, lower alkyl-thio, hydroxy,hydroxymethyl or lower alkanoyl; or pharmaceutically acceptable saltsthereof.
 5. The compound of claim 1, wherein R¹, R⁴, and n are asdefined in claim 1, X, Y and Z represent oxygen, Q represents—(CH₂)_(k)— with k=2 or 3, R² represents heteroaryl and R³ representsphenyl or mono-substituted phenyl substituted with halogen, lower alkyl,lower alkenyl, lower alkoxy, amino, lower alkyl-amino, lower alkyl-thio,hydroxy, hydroxymethyl or lower alkanoyl; or pharmaceutically acceptablesalts thereof.
 6. The compound of claim 1, wherein R¹, R⁴, and n are asdefined in claim 1, X, Y and Z represent oxygen, Q represents —(CH₂)₂—,R² represents heteroaryl, R³ represents phenyl or mono-substitutedphenyl substituted with halogen, lower alkyl, lower alkenyl, methoxy,amino, lower alkyl-amino, lower alkyl-thio, hydroxy, hydroxymethyl orlower alkanoyl; or pharmaceutically acceptable salts thereof.
 7. Acompound of formula II

wherein R¹, R², R³, R⁴, Y, Q, Z and n are as defined in claim 1 above,or pharmaceutically acceptable salts thereof.
 8. A compound of formulaIII

wherein R¹, R², R⁴, Y, Q, Z and n are as defined in claim 1 above, orpharmaceutically acceptable salts thereof.
 9. A compound of formula IV

wherein R¹, R², R⁴, Q and n are as defined in claim 1 above, orpharmaceutically acceptable salts thereof.
 10. A compound of formula V

wherein R¹, R² and n are as defined in claim 1 above, orpharmaceutically acceptable salts thereof.
 11. The compound of claim 10,wherein R² in formula V represents heteroaryl or pharmaceuticallyacceptable salts thereof.
 12. The compound of claim 1 wherein saidcompound is selected from the group consisting of:2-Phenyl-ethanesulfonic acid{6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide, 2-Phenyl-ethanesulfonic acid{6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-[2,2′]bipyrimidinyl-4-yl}-amide,2-Phenyl-ethanesulfonic acid{5-(2-methoxy-phenoxy)-6-[2-(pyrimidin-2-yloxy)-ethoxy]-[2,2′]bipyrimidinyl-4-yl}-amide,2-Phenyl-ethanesulfonic acid{5-(2-methoxy-phenoxy)-6-[2-(5-methoxy-pyrimidin-2-yloxy)-ethoxy]-[2,2′]bipyrimidinyl-4-yl}-amide,2-Thiophen-2-yl-ethanesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide,2-Thiophen-2-yl-ethanesulfonic acid{5-(4-chloro-phenyl)-6-[2-(5-methoxy-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide, 2-Pyridin-2-yl-ethanesulfonicacid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide,and pharmaceutically acceptable salts thereof.
 13. A pharmaceuticalcomposition comprising one or more of the compounds of any one of claims1, 7, 8, 9 and 10 and a pharmaceutically acceptable carrier.
 14. Aprocess for preparing a pharmaceutical composition, comprising mixingone or more compounds of any one of claims 1, 7, 8, 9 and 10 with apharmaceutically acceptable carrier.